8XV4

Crystal structure of TTD-PHD domain of UHRF1 in complex with mStella peptide (residues 85-119)

Summary for 8XV4

• Entry DOI: 10.2210/pdb8xv4/pdb
• Descriptor: E3 ubiquitin-protein ligase UHRF1, Developmental pluripotency-associated protein 3, ZINC ION, ... (4 entities in total)
• Functional Keywords: uhfr1, stella, complex, inhibitor, gene regulation, gene regulation-inhibitor complex, gene regulation/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 61970.02

Authors

Du, X.,Gan, Q.,Xu, J.,Liu, J. (deposition date: 2024-01-14, release date: 2024-11-06, Last modification date: 2025-02-19)

Primary citation

Bai, W.,Xu, J.,Gu, W.,Wang, D.,Cui, Y.,Rong, W.,Du, X.,Li, X.,Xia, C.,Gan, Q.,He, G.,Guo, H.,Deng, J.,Wu, Y.,Yen, R.C.,Yegnasubramanian, S.,Rothbart, S.B.,Luo, C.,Wu, L.,Liu, J.,Baylin, S.B.,Kong, X.
Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy.
Nat Commun, 16:474-474, 2025

PubMed Abstract: UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity.

PubMed: 39774694
DOI: 10.1038/s41467-024-55481-7

Experimental method

X-RAY DIFFRACTION (3.2 Å)